tbuckley/cabot-search huggingface dataset:
Abstract 4846: Mitochondria packaged from platelet-derived microvesicles modulate the metabolism and mitochondrial dynamics of breast cancer cells
Authors: Vanessa L. Gauvin, Vanessa Veilleux, Nicolas Pichaud, Gilles A. Robichaud, Luc H. Boudreau
Journal: Cancer Research (2023)

Abstract The incidence of breast cancer among women far exceeds those of other cancers where metastasis accounts for the majority of deaths associated with the disease. It is well established that platelets play a prominent role in breast cancer malignancy and disease progression. Recently, activated platelets have been characterized to release platelet-derived microparticles (PMPs), which can also package functional mitochondria of platelet origin (termed mitoMPs). We recently demonstrated that mitoMPs can interact with breast cancer cells where they transfer their cargo (i.e., mitochondria) to recipient cancer cells upon their internalization. Given that metabolic reprogramming through mitochondrial dynamics represents a hallmark trait of cancer progression, the intercellular trafficking of foreign mitochondria provided by mitoMPs represent a new mechanistic avenue for cancer cell metabolic plasticity and disease progression.Therefore, the aim of this study was to evaluate the impact of mitoMP-packaged mitochondria on recipient breast cancer cell mitochondrial dynamics upon internalization. Technically, a series of breast cancer cell models (MB231, MCF7 and MCF10A) were co-cultured with mitoMPs and profiled for mitochondrial dynamics and function using complementing experimental approaches, such as flow cytometry, confocal microscopy, and RT-qPCR. We show that mitoMPs and their mitochondria cargo internalize primarily into the malignant MB231 cell model. To investigate the impact of mitoMP uptake by cancer cells on the mitochondrial dynamics, RT-qPCR and Western blot analyses were performed to profile the expression levels of several fusion and fission proteins, including OPA1, MFF, DRP1, MitoFusin 1 and MitoFusin 2. Finally, using fluorescent-based assays, we confirmed that mitoMPs modulated ATP production in MB231 breast cancer cells through upregulation of the OXPHOS pathway. Our research provides a new mechanism by which extracellular vesicles (mitoMPs) play an important role in cancer cell mitochondrial dynamics and function to support metabolic plasticity during the metastatic journey of cancer cells. The knowledge gained from these studies will further provide new avenues for strategic intervention to mitigate the morbidity and mortality associated with breast cancer disease. Citation Format: Vanessa L. Gauvin, Vanessa Veilleux, Nicolas Pichaud, Gilles A. Robichaud, Luc H. Boudreau. Mitochondria packaged from platelet-derived microvesicles modulate the metabolism and mitochondrial dynamics of breast cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4846.
Abstract 1544: MBK-103, a potent novel conjugation platform-based antibody-drug conjugate, changing therapeutic options in folate receptor alpha positive cancer patients
Authors: Warren Viricel, Louise Conilh, Edouard Leroy, Jean-Guillaume Lafay, Frederique Brune, Lenka Kyrych Sadilkova, Charles Dumontet
Journal: Cancer Research (2023)

Abstract Folate receptor alpha (FOLR1) is a clinically validated target, that is overexpressed extracellularly in numerous solid malignancies with a high unmet medical need. Ovarian, non-small cell lung and breast adenocarcinomas are among indications with the highest frequency of FOLR1-positive patients with one out of two patients showing upregulated topoisomerase I expression. MBK-103, an antibody-drug conjugate targeting FOLR1, is based on Mablink’s novel proprietary hydrophilic drug-linker platform. It is comprised of: (i) an Fc-attenuated humanized IgG1 monoclonal antibody, that selectively binds to FOLR1; (ii) a polysarcosine hydrophobicity masking entity allowing for a high drug-to-antibody ratio (DAR) of 8, while improving the pharmacokinetics and tolerability of the drug; (iii) a proprietary dipeptide cleavable unit and iv) exatecan, a potent topoisomerase I inhibitor. MBK-103 showed excellent ex vivo stability in human plasma enabling a prolonged half-life, similar to that of the unconjugated monoclonal antibody. This led to an increased drug exposure, resulting in a potent antitumor efficacy observed in a collection of more than ten in vivo mouse tumor models with a diverse FOLR1 expression, already at doses as low as 1-3 mg/kg. In addition, the distinct mode of action of exatecan along with the unique characteristics of the proprietary drug-linker platform resulted in the in vivo antitumor potency obtained also in colorectal cancer models, in which tubulin-inhibiting agents exhibit only limited therapeutic effects. The compound was also very well tolerated in cynomolgus monkeys with HNSTD at 50 mg/kg and even when administered repeatedly. High conjugation yields along with 100% homogeneity are major drivers of the successful ongoing manufacturing process with planned IND submission in Q4/2023. Citation Format: Warren Viricel, Louise Conilh, Edouard Leroy, Jean-Guillaume Lafay, Frederique Brune, Lenka Kyrych Sadilkova, Charles Dumontet. MBK-103, a potent novel conjugation platform-based antibody-drug conjugate, changing therapeutic options in folate receptor alpha positive cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1544.
CD22 CAR T-cell associated hematologic toxicities, endothelial activation and relationship to neurotoxicity
Authors: Jennifer Jess, Bonnie Yates, Alina Dulau-Florea, Kevin Parker, Jon Inglefield, Dan Lichtenstein, Fiorella Schischlik, Martin Ongkeko, Yanyu Wang, Shilpa Shahani, Ann Cullinane, Hannah Smith, Eli Kane, Lauren Little, Dong Chen, Terry J Fry, Haneen Shalabi, Hao-Wei Wang, Ansuman Satpathy, Jay Lozier, Nirali N Shah
Journal: Journal for ImmunoTherapy of Cancer (2023)

Hematologic toxicities, including coagulopathy, endothelial activation, and cytopenias, with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies correlate with cytokine release syndrome (CRS) and neurotoxicity severity, but little is known about the extended toxicity profiles of CAR T-cells targeting alternative antigens. This report characterizes hematologic toxicities seen following CD22 CAR T-cells and their relationship to CRS and neurotoxicity.
Delirium prevention with age consideration—Reply to “Comment on Yang et al., 2020: Melatonergic agents in the prevention of delirium: A network meta-analysis of randomized controlled trials”
Authors: Chun-Pai Yang, Ping-Tao Tseng, Cheng-Chia Yang, I-Ju Tsai, Kuan-Pin Su
Journal: Sleep Medicine Reviews (2023)
Abstract ND01: ABBV-319: A first-in-class Glucocorticoid Receptor Modulator (GRM) agonist ADC for the treatment of B-cell malignancies
Authors: James W. Purcell
Journal: Cancer Research (2023)

Abstract ABBV-319 is a novel CD19-targeting multi-modal antibody drug conjugate (ADC) for the treatment of B-cell malignancies. The ADC is engineered to have 3 distinct mechanisms of action to maximize anti-cancer activity while reducing systemic toxicities: (1) targeted GRM payload delivery, (2) signaling inhibition of CD19/BCR and (3) enhanced ADCC via afucosylation. Unlike traditional cytotoxic ADCs, the GRM payload is a high potency agonist (sub nM EC50) of the intracellular glucocorticoid receptor (GR) which then traffics to the nucleus resulting in sustained GR-driven transcriptional events leading to cancer cell death. CD19 is a clinically validated B-cell target (approved antibodies, ADCs, CARTs) known to be highly expressed even following multiple lines of therapy, making it an appropriate target for this novel approach. The CD19 antibody in ABBV-319 is an optimized high affinity IgG1 that can inhibit CD19/BCR downstream signaling events including AKT, leading to inhibition of growth in certain B-cell lines. Given ADCC/ADCP is a highly effective mechanism in B-cell malignancies (e.g., rituximab, tafasitamab) the CD19 antibody was engineered to have increased FcγR binding via afucosylation, that retains its enhanced ADCC activity as a GRM drug conjugate. By engineering the molecule in this way, the multi-modal ADC is not solely reliant on one mechanism of action for activity and therefore has the potential for broader activity. Sustained regressions/cures have been observed in multiple B-cell malignancy xenograft model systems (cell-line, PDX, humanized) after a single ADC dose that compares favorably against approved benchmark antibodies, systemic steroids and ADCs. ABBV-319 targets clinically validated mechanisms of action that are known to combine well with multiple standard-of-care agents. This combination potential together with its favorable safety profile, suggests ABBV-319 will be a highly effective combination treatment for B-cell malignancies. ABBV-319 was well tolerated in cynomolgus monkey studies with favorable drug-like properties and antibody-like pharmacokinetics, enabling a high mg/kg clinical starting dose. A first in-human Phase 1 clinical trial evaluating ABBV-319 in B-cell malignancies (DLBCL, FL, CLL) was recently initiated in late 2022 (clinicaltrials.gov, NCT05512390). Citation Format: James W. Purcell. ABBV-319: A first-in-class Glucocorticoid Receptor Modulator (GRM) agonist ADC for the treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND01.
Abstract ND09: M3913 induces the maladaptive unfolded protein response through a novel mechanism resulting in strong anti-tumor activity
Authors: Frank Czauderna, Richard Schneider, Shivapriya Ramaswamy, Susanne Brandstetter, Elise Drouin, Olga Bogatyrova, Johanna Mazur, Qing Sun, Catherine Jorand-Lebrun, Eva Sherbetjian, Jonny Nachtigall, Carolyn Wing, Christian Hildebrand, Peter Ellinghaus, Isabelle Lemoine, Mac Johnson, Russell Hoover, Michael Clark, Ralph Lindemann
Journal: Cancer Research (2023)

Abstract Therapeutic strategies based on exacerbated stress signaling may represent novel and effective treatment paradigms in oncology. Here, we disclose for the first time the endoplasmic reticulum (ER) stress modulator (ERSM) M3913 that was discovered and developed following a phenotypic screening campaign. Mechanistically, M3913 engages an ER transmembrane protein not yet implicated in cancer biology to induce a Ca2+ shift from the ER towards the cytoplasm, resulting in an unfolded protein response and subsequent antitumor activity in sensitive preclinical models. We detected concurrent elevation of bona fide ER stress markers by several methods including qRT-PCR, Western Blotting analysis, and unbiased transcriptome analysis. Genetic removal of M3913’s putative ER transmembrane target abrogated the M3913-mediated, but not the Thapsigargin-mediated, ER stress response. PK/PD studies confirmed a dose- and time-dependent upregulation of ER stress markers in preclinical cancer models in vivo. As a monotherapy, M3913 induced full and partial tumor regression in preclinical models of multiple myeloma, non-small-cell lung cancer, triple-negative breast cancer, and other cancers. An in vitro combination screen indicated combination potential of M3913 with standard-of-care agents and novel candidate drugs. IND-enabling toxicology and additional mechanism-of-action studies in rat and minipig uncovered specific target organs for M3913 in line with expression of the target in human tissues. This presentation details mechanistic profiling data from M3913, reveals its putative ER-resident target and discusses forward translation studies that support M3913 as a novel therapeutic option for hard-to-treat subtypes of a variety of cancers. Citation Format: Frank Czauderna, Richard Schneider, Shivapriya Ramaswamy, Susanne Brandstetter, Elise Drouin, Olga Bogatyrova, Johanna Mazur, Qing Sun, Catherine Jorand-Lebrun, Eva Sherbetjian, Jonny Nachtigall, Carolyn Wing, Christian Hildebrand, Peter Ellinghaus, Isabelle Lemoine, Mac Johnson, Russell Hoover, Michael Clark, Ralph Lindemann. M3913 induces the maladaptive unfolded protein response through a novel mechanism resulting in strong anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND09.
Abstract ND10: Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers
Authors: Owen B. Wallace, Gerald Gavory, Mahmoud Ghandi, Anne-Cecile d’Alessandro, Debora Bonenfant, Maciej Cabanski, Lisa Cantagallo, Agustin Chicas, Qian Chen, Anna Diesslin, Christopher King, Vittoria Massafra, Rajiv Narayan, Arnaud Osmont, Dave Peck, Carolina Perdomo Ortiz, Martin Schillo, Ambika Singh, Ralph Tiedt, Simone Tortoioli, Silvia Buonamici, Markus Warmuth, Filip Janku, Bernhard Fasching
Journal: Cancer Research (2023)

Abstract MYC transcription factors have been demonstrated to be drivers of many cancers, yet have remained recalcitrant to new drug development. We hypothesized that MYC-driven cancer cell lines are addicted to protein translation, and therefore are vulnerable to the loss of the translation termination factor, GSPT1. We have discovered MRT-2359, a selective GSPT1 molecular glue degrader, that demonstrates potent and preferential antiproliferative activity in MYC-driven cell lines, such as high N- and L-MYC mRNA expressing non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) lines. MRT-2359 has been optimized for differential toxicity between MYC- and non-MYC-driven cancer cell lines, kinetics and depth of degradation, oral bioavailability, and in vivo efficacy. The anti-tumor activity of MRT-2359 was assessed in more than 80 lung patient-derived xenografts (PDXs) that confirmed the preferential anti-tumor activity in N- and L-MYC high NSCLC and SCLC PDXs when dosed orally daily or intermittently. Similar levels of activity were also observed in neuroendocrine lung cancer PDXs and lymphoma models. Oral MRT-2359 is currently in a Phase 1/2 clinical trial in selected cancer patients with MYC-driven NSCLC, SCLC, high grade neuroendocrine cancers and diffuse large B-cell lymphoma (NCT05546268). Citation Format: Owen B. Wallace, Gerald Gavory, Mahmoud Ghandi, Anne-Cecile d’Alessandro, Debora Bonenfant, Maciej Cabanski, Lisa Cantagallo, Agustin Chicas, Qian Chen, Anna Diesslin, Christopher King, Vittoria Massafra, Rajiv Narayan, Arnaud Osmont, Dave Peck, Carolina Perdomo Ortiz, Martin Schillo, Ambika Singh, Ralph Tiedt, Simone Tortoioli, Silvia Buonamici, Markus Warmuth, Filip Janku, Bernhard Fasching. Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND10.
Abstract ND06: AMG 305, a dual targeting BiTE®molecule with selective activity for solid tumors that co-express CDH3 and MSLN
Authors: Elizabeth Pham, Petra Lutterbuese, Petra Deegen, Natalie Mariano, Katja Matthes, Joachim Wahl, Pamela Bogner, Joan Lane, Kristin Lewis Wilson, Rodolfo Yabut, Virginie Naegele, Ines Ullrich, Stephanie Everts, Markus Muenz, Thomas Boehm, Sabine Stienen, Angela Coxon, Peter Kufer, Tobias Raum, Julie M. Bailis
Journal: Cancer Research (2023)

Abstract T cell engager (TCE) molecules are a targeted immune therapy that redirect a patient’s T cells to kill tumor cells. While several TCE molecules have now advanced to approval, clinical development has been challenging, especially in the solid tumor setting. There are few solid tumor surface antigens that are tumor-specific, and antigens with even low levels of expression in normal tissue can be recognized by a TCE and result in on-target off-tumor toxicity. To overcome this challenge, we have developed AMG 305, a first-in-class, dual targeting BiTE® (bispecific T cell engager) molecule that requires binding to both P-cadherin (CDH3) and mesothelin (MSLN) for potent cytotoxic activity. Immunohistochemistry analysis shows that CDH3 and MSLN are co-expressed in multiple solid tumor types. In normal tissues, immunostaining shows fewer tissues have overlapping co-expression than expression of just one or the other target. AMG 305 relies on an avidity-based approach to engage T cells to preferentially kill CDH3+MSLN+ tumor cells, with limited activity against normal cells that express only one of the target antigens. In vitro, AMG 305 induces potent cytotoxicity against tumor cells co-expressing CDH3 and MSLN, with greatly attenuated activity against cells expressing only CDH3 or MSLN. In vivo, AMG 305 demonstrates dose-dependent antitumor activity in a CDH3+MSLN+ xenograft tumor model. AMG 305 was clinically well-tolerated in a nonclinical safety study in cynomolgus monkey. Data from IND-enabling preclinical studies support initiation of the first-in-human study of AMG 305 in CDH3+MSLN+ solid tumors in 2023. Citation Format: Elizabeth Pham, Petra Lutterbuese, Petra Deegen, Natalie Mariano, Katja Matthes, Joachim Wahl, Pamela Bogner, Joan Lane, Kristin Lewis Wilson, Rodolfo Yabut, Virginie Naegele, Ines Ullrich, Stephanie Everts, Markus Muenz, Thomas Boehm, Sabine Stienen, Angela Coxon, Peter Kufer, Tobias Raum, Julie M. Bailis. AMG 305, a dual targeting BiTE®molecule with selective activity for solid tumors that co-express CDH3 and MSLN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND06.
Abstract 1470: ASCL1 dimerizes with TCF12 protein and activates BMP-SMAD1 pathway during subtype switching from mesenchymal towards adrenergic neuroblastoma
Authors: Lu Wang, Tze King Tan, Hyoju Kim, Dennis Kappei, Shi Hao Tan, A. Thomas Look, Takaomi Sanda
Journal: Cancer Research (2023)

Abstract Recently, several studies have demonstrated two semi-stable and interchangeable subtypes of neuroblastoma, namely mesenchymal (MES) and adrenergic (ADRN) subtypes, which are associated with the early neural crest and committed adrenergic neural progenitor stages, respectively. Each of these subtypes is controlled by a different set of transcription factors forming the core regulatory circuit (CRC) and exhibits different enhancer and transcription profiles. However, transcription factors that drives transition of the subtype switching and the corresponding regulated signaling pathways remain to be investigated. In this study, we demonstrate that ASCL1, a critical member of the ADRN CRC, can induce a subtype switching from MES to ADRN neuroblastoma. Our study shows that a forced expression of ASCL1 in MES neuroblastoma cells results in cell cycle arrest and cell differentiation towards the ADRN lineage with induction of ADRN gene expression, such as DLL3 and DBH. Furthermore, we have identified TCF12 as an important interaction partner of ASCL1 via SILAC analysis. ASCL1 forms a complex with TCF12 and regulates the expression of downstream target genes. On the other hand, overexpression of ASCL1 inhibits existing MES specific TGFβ-SMAD2/3 signaling pathway, while it activates BMP-SMAD1 signaling pathway. Interestingly, activation of BMP-SMAD1 signaling pathway results in the upregulation of the ID proteins, which can form dimer with TCF12 protein and sequester it away from ASCL1 protein. Thus, the BMP SMAD1-ID protein signaling cascade in turn serves as a negative feedback loop to prevent the cells from terminal differentiation via equilibration of the amount of ASCL1-TCF12 dimer. In summary, ASCL1 can induce the subtype switching and partially define the ADRN transcription program. ASCL1 serves as a lineage master initiator that characterizes ADRN neuroblastoma. Citation Format: Lu Wang, Tze King Tan, Hyoju Kim, Dennis Kappei, Shi Hao Tan, A. Thomas Look, Takaomi Sanda. ASCL1 dimerizes with TCF12 protein and activates BMP-SMAD1 pathway during subtype switching from mesenchymal towards adrenergic neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1470.
Abstract ND11: EO-3021: An antibody drug conjugate targeting CLDN18.2 expressing cancers
Authors: David Dornan
Journal: Cancer Research (2023)

Abstract Claudin 18.2 is tight junction protein with a highly selective cell surface expression profile that is limited to the normal gastric mucosa. Importantly, it is often overexpressed in several types of cancers including gastric, pancreatic, esophageal, ovarian, and lung. There are currently no approved targeted therapies for claudin 18.2-expressing cancers. As such, we designed an antibody drug conjugate, EO-3021/SYSA1801 with the potential to selectively target and kill claudin 18.2-expressing cancer cells. EO-3021 is comprised of a novel tumor-targeting monoclonal antibody that selectively binds claudin 18.2 (Kd = 0.6 nM) that is conjugated to monomethyl auristatin E (MMAE). EO-3021 is internalized in claudin 18.2-expressing cells as well as demonstrates cell killing across a range of cancer cell lines with low (IC50 = 228 ng/ml), medium (IC50 = 7 ng/ml), and high levels of claudin 18.2 (IC50 = 28 ng/ml) expression. More specifically, claudin 18.2-expressing cells undergo G2/M cell cycle arrest and apoptosis upon EO-3021 treatment. EO-3021 demonstrates tumor regressions with a single dose across low, medium, and high claudin 18.2-expressing in vivo models derived from pancreatic (9 mg/kg), gastric (2 mg/kg), and lung cancers (8 mg/kg), respectively. In addition, a single dose of EO-3021 outperforms standard of care chemotherapies, such as cisplatin and gemcitabine, across in vivo models. Nonclinical toxicology studies suggested that EO-3021-mediated toxicities were reversible and manageable as well as afford a therapeutic index suitable for testing in humans. EO-3021/SYSA1801 is currently being evaluated in a Phase I dose escalation study (NCT05009966) in patients with claudin 18.2 positive advanced malignant solid tumors. A case study will be presented where a confirmed and durable partial response (66.7% tumor reduction) was observed following EO-3021 treatment. Citation Format: David Dornan. EO-3021: An antibody drug conjugate targeting CLDN18.2 expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND11.